Digital Commons Network^™

Assessing Potentiation Of The (Α4)3(Β2)2 Nicotinic Acetylcholine Receptor By The Allosteric Agonist Cmpi, Farah Deba, Kemburli Munoz, Eloisa Peredia, Gustav Akk, Ayman K Hamouda

Open Access Publications

The extracellular domain of the nicotinic acetylcholine receptor isoforms formed by three α4 and two β2 subunits ((α4)3(β2)2 nAChR) harbors two high-affinity "canonical" acetylcholine (ACh)-binding sites located in the two α4:β2 intersubunit interfaces and a low-affinity "noncanonical" ACh-binding site located in the α4:α4 intersubunit interface. In this study, we used ACh, cytisine, and nicotine (which bind at both the α4:α4 and α4:β2 interfaces), TC-2559 (which binds at the α4:β2 but not at the α4:α4 interface), and 3-(2-chlorophenyl)-5-(5-methyl-1-(piperidin-4-yl)-1H-pyrrazol-4-yl)isoxazole (CMPI, which binds at the α4:α4 but not at the α4:β2 interface), to investigate the binding and gating properties of CMPI at the …

Understanding Contributors To Racial And Ethnic Inequities In Covid-19 Incidence And Mortality Rates, Karen E. Joynt Maddox, Mat Reidhead, Joshua Grotzinger, Timothy Mcbride, Aaloke Mody, Elna Nagasako, Will Ross, Joseph T. Steensma, Abigail R. Barker

Open Access Publications

BACKGROUND: Racial inequities in Coronavirus 2019 (COVID-19) have been reported over the course of the pandemic, with Black, Hispanic/Latinx, and Native American individuals suffering higher case rates and more fatalities than their White counterparts.

METHODS: We used a unique statewide dataset of confirmed COVID-19 cases across Missouri, linked with historical statewide hospital data. We examined differences by race and ethnicity in raw population-based case and mortality rates. We used patient-level regression analyses to calculate the odds of mortality based on race and ethnicity, controlling for comorbidities and other risk factors.

RESULTS: As of September 10, 2020 there were 73,635 confirmed …

High Temporal Resolution Measurements Of Movement Reveal Novel Early-Life Physiological Decline In C. Elegans, Drew Benjamin Sinha, Zachary Scott Pincus

Open Access Publications

Age-related physiological changes are most notable and best-studied late in life, while the nature of aging in early- or middle-aged individuals has not been explored as thoroughly. In C. elegans, many studies of movement vs. age generally focus on three distinct phases: sustained, youthful movement; onset of rapidly progressing impairment; and gross immobility. We investigated whether this first period of early-life adult movement is a sustained "healthy" level of high function followed by a discrete "movement catastrophe"-or whether there are early-life changes in movement that precede future physiological declines. To determine how movement varies during early adult life, we followed …

Advances And Gaps In Sars-Cov-2 Infection Models, César Muñoz-Fontela, Michael S. Diamond, Et Al

Open Access Publications

The global response to Coronavirus Disease 2019 (COVID-19) is now facing new challenges such as vaccine inequity and the emergence of SARS-CoV-2 variants of concern (VOCs). Preclinical models of disease, in particular animal models, are essential to investigate VOC pathogenesis, vaccine correlates of protection and postexposure therapies. Here, we provide an update from the World Health Organization (WHO) COVID-19 modeling expert group (WHO-COM) assembled by WHO, regarding advances in preclinical models. In particular, we discuss how animal model research is playing a key role to evaluate VOC virulence, transmission and immune escape, and how animal models are being refined to …

Sarm1 Activation Produces Cadpr To Increase Intra-Axonal Ca++ And Promote Axon Degeneration In Pipn, Yihang Li, Maria F. Pazyra-Murphy, Daina Avizonis, Mariana De Sá Tavares Russo, Sophia Tang, Chiung-Ya Chen, Yi-Ping Hsueh, Johann S. Bergholz, Tao Jiang, Jean J. Zhao, Jian Zhu, Kwang Woo Ko, Jeffrey Milbrandt, Aaron Diantonio, Rosalind A. Segal

Open Access Publications

Cancer patients frequently develop chemotherapy-induced peripheral neuropathy (CIPN), a painful and long-lasting disorder with profound somatosensory deficits. There are no effective therapies to prevent or treat this disorder. Pathologically, CIPN is characterized by a "dying-back" axonopathy that begins at intra-epidermal nerve terminals of sensory neurons and progresses in a retrograde fashion. Calcium dysregulation constitutes a critical event in CIPN, but it is not known how chemotherapies such as paclitaxel alter intra-axonal calcium and cause degeneration. Here, we demonstrate that paclitaxel triggers Sarm1-dependent cADPR production in distal axons, promoting intra-axonal calcium flux from both intracellular and extracellular calcium stores. Genetic or …

The 2021 Faseb Science Research Conference On Nad Metabolism And Signaling, Vera Gorbunova, Shin-Ichiro Imai, Et Al

Open Access Publications

No abstract provided.

Epigenetic Regulation Of Human T‐Cell Leukemia Virus Gene Expression, Lee Ratner

Open Access Publications

No abstract provided.

Severe Ocrelizumab-Induced Enterocolitis Treated Successfully With Ustekinumab, Janaki Shah, Ahmad Al-Taaee, Parakkal Deepak, Anas Gremida

Open Access Publications

No abstract provided.

M6a Modifications Regulate Intestinal Immunity And Rotavirus Infection, Anmin Wang, Gaopeng Hou, Siyuan Ding, Et Al

Open Access Publications

N6-methyladenosine (m6A) is an abundant mRNA modification and affects many biological processes. However, how m6A levels are regulated during physiological or pathological processes such as virus infections, and the in vivo function of m6A in the intestinal immune defense against virus infections are largely unknown. Here, we uncover a novel antiviral function of m6A modification during rotavirus (RV) infection in small bowel intestinal epithelial cells (IECs). We found that rotavirus infection induced global m6A modifications on mRNA transcripts by down-regulating the m6a eraser ALKBH5. Mice lacking the m6A writer enzymes METTL3 in IECs (

A Test Of The Pioneer Factor Hypothesis Using Ectopic Liver Gene Activation, Jeffrey L. Hansen, Kaiser J. Loell, Barak A. Cohen

Open Access Publications

The pioneer factor hypothesis (PFH) states that pioneer factors (PFs) are a subclass of transcription factors (TFs) that bind to and open inaccessible sites and then recruit non-pioneer factors (non-PFs) that activate batteries of silent genes. The PFH predicts that ectopic gene activation requires the sequential activity of qualitatively different TFs. We tested the PFH by expressing the endodermal PF FOXA1 and non-PF HNF4A in K562 lymphoblast cells. While co-expression of FOXA1 and HNF4A activated a burst of endoderm-specific gene expression, we found no evidence for a functional distinction between these two TFs. When expressed independently, both TFs bound and …

The Mutationathon Highlights The Importance Of Reaching Standardization In Estimates Of Pedigree-Based Germline Mutation Rates, Lucie A. Bergeron, Tychele Turner, Et Al

Open Access Publications

In the past decade, several studies have estimated the human per-generation germline mutation rate using large pedigrees. More recently, estimates for various nonhuman species have been published. However, methodological differences among studies in detecting germline mutations and estimating mutation rates make direct comparisons difficult. Here, we describe the many different steps involved in estimating pedigree-based mutation rates, including sampling, sequencing, mapping, variant calling, filtering, and appropriately accounting for false-positive and false-negative rates. For each step, we review the different methods and parameter choices that have been used in the recent literature. Additionally, we present the results from a 'Mutationathon,' a …

Intrinsic Mechanisms In The Gating Of Resurgent Na+ Currents, Joseph L. Ransdell, Jonathan D. Moreno, Druv Bhagavan, Jonathan R. Silva, Jeanne M. Nerbonne

Open Access Publications

The resurgent component of the voltage-gated sodium current (I

Tumor Lysis Syndrome In A Patient With Metastatic Endometrial Cancer Treated With Lattice Stereotactic Body Radiation Therapy, Joshua P Schiff, Matthew B Spraker, Sai Duriseti, Sana Shaikh, Haris F Murad, David G Mutch, Clifford G Robinson, James Kavanaugh, Alexander J Lin

Open Access Publications

No abstract provided.

Perceptions Of Risk Of Sars-Cov-2 Transmission In Social And Educational Activities By Infectious Diseases And General Pediatric Healthcare Providers, A Pre-Vaccine Risk Perception Cross-Sectional Survey, Andrew B. Janowski, Philip M. Polgreen, Susan E. Beekmann, Jason G. Newland

Open Access Publications

BACKGROUND: The perception of the transmission risks of SARS-CoV-2 in social and educational settings by US healthcare providers have not been previously quantified.

METHODS: Respondents completed an online survey between September and October 2020 to estimate the risk of SARS-CoV-2 transmission on a scale of 0-10 for different social and educational activities prior to the availability of the SARS-CoV-2 vaccines. Demographic information and experiences during the pandemic were also collected. The risk assessment was emailed to three listservs of healthcare providers, including national listservs of pediatric (PID) and adult infectious diseases (AID) providers, and a listserv of general pediatric practitioners …

Loss Of Kmt2c Reprograms The Epigenomic Landscape In Hpscs Resulting In Nodal Overexpression And A Failure Of Hemogenic Endothelium Specification, Shailendra Maurya, Wei Yang, Minori Tamai, Qiang Zhang, Petra Erdmann-Gilmore, Amelia Bystry, Fernanda Martins Rodrigues, Mark C Valentine, Wing H Wong, Reid Townsend, Todd E Druley

Open Access Publications

Germline or somatic variation in the family of KMT2 lysine methyltransferases have been associated with a variety of congenital disorders and cancers. Notably,

Augmented Cardiac Growth Hormone Signaling Contributes To Cardiomyopathy Following Genetic Disruption Of The Cardiomyocyte Circadian Clock, Ravi Sonkar, Ryan Berry, Mary N Latimer, Sumanth D Prabhu, Martin E Young, Stuart J Frank

Open Access Publications

Circadian clocks regulate numerous biological processes, at whole body, organ, and cellular levels. This includes both hormone secretion and target tissue sensitivity. Although growth hormone (GH) secretion is time-of-day-dependent (increased pulse amplitude during the sleep period), little is known regarding whether circadian clocks modulate GH sensitivity in target tissues. GH acts in part through induction of insulin-like growth factor 1 (IGF1), and excess GH/IGF1 signaling has been linked to pathologies such as insulin resistance, acromegaly, and cardiomyopathy. Interestingly, genetic disruption of the cardiomyocyte circadian clock leads to cardiac adverse remodeling, contractile dysfunction, and reduced lifespan. These observations led to the …

Isolation Of Sars-Cov-2 In Viral Cell Culture In Immunocompromised Patients With Persistently Positive Rt-Pcr Results, Abby Sung, Adam L Bailey, Henry B Stewart, David Mcdonald, Meghan A Wallace, Kate Peacock, Candace Miller, Kimberly A Reske, Caroline A O'Neil, Victoria J Fraser, Michael S Diamond, Carey-Ann D Burnham, Hilary M Babcock, Jennie H Kwon

Open Access Publications

Immunocompromised adults can have prolonged acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive RT-PCR results, long after the initial diagnosis of coronavirus disease 2019 (COVID-19). This study aimed to determine if SARS-CoV-2 virus can be recovered in viral cell culture from immunocompromised adults with persistently positive SARS-CoV-2 RT-PCR tests. We obtained 20 remnant SARS-CoV-2 PCR positive nasopharyngeal swabs from 20 immunocompromised adults with a positive RT-PCR test ≥14 days after the initial positive test. The patients' 2

Nia Long Life Family Study: Objectives, Design, And Heritability Of Cross-Sectional And Longitudinal Phenotypes, Mary K. Wojczynski, Shiow Jiuan Lin, Paola Sebastiani, Thomas T. Perls, Joseph Lee, Alexander Kulminski, Anne Newman, Joe M. Zmuda, Kaare Christensen, Michael A. Province

Open Access Publications

The NIA Long Life Family Study (LLFS) is a longitudinal, multicenter, multinational, population-based multigenerational family study of the genetic and nongenetic determinants of exceptional longevity and healthy aging. The Visit 1 in-person evaluation (2006-2009) recruited 4 953 individuals from 539 two-generation families, selected from the upper 1% tail of the Family Longevity Selection Score (FLoSS, which quantifies the degree of familial clustering of longevity). Demographic, anthropometric, cognitive, activities of daily living, ankle-brachial index, blood pressure, physical performance, and pulmonary function, along with serum, plasma, lymphocytes, red cells, and DNA, were collected. A Genome Wide Association Scan (GWAS) (Ilumina Omni 2.5M …

Dysregulation Of The Leukocyte Signaling Landscape During Acute Covid-19, Isaiah R. Turnbull, Anja Fuchs, Kenneth E. Remy, Michael P. Kelly, Elfaridah P. Frazier, Sarbani Ghosh, Shin-Wen Chang, Monty B. Mazer, Annie Hess, Jennifer M. Leonard, Mark H. Hoofnagle, Marco Colonna, Richard S. Hotchkiss

Open Access Publications

The global COVID-19 pandemic has claimed the lives of more than 750,000 US citizens. Dysregulation of the immune system underlies the pathogenesis of COVID-19, with inflammation mediated tissue injury to the lung in the setting of suppressed systemic immune function. To define the molecular mechanisms of immune dysfunction in COVID-19 we utilized a systems immunology approach centered on the circulating leukocyte phosphoproteome measured by mass cytometry. We find that although COVID-19 is associated with wholesale activation of a broad set of signaling pathways across myeloid and lymphoid cell populations, STAT3 phosphorylation predominated in both monocytes and T cells. STAT3 phosphorylation …

Steroid Hormone Signaling Activates Thermal Nociception During Drosophila Peripheral Nervous System Development, Jacob S. Jaszczak, Laura Devault, Lily Yeh Jan, Yuh Nung Jan

Open Access Publications

Sensory neurons enable animals to detect environmental changes and avoid harm. An intriguing open question concerns how the various attributes of sensory neurons arise in development.

Fracture Healing Is Delayed In The Absence Of Gasdermin-Interleukin-1 Signaling, Kai Sun, Chun Wang, Jianqiu Xiao, Michael D. Brodt, Luorongxin Yuan, Tong Yang, Yael Alippe, Huimin Hu, Dingjun Hao, Yousef Abu-Amer, Matthew J. Silva, Jie Shen, Gabriel Mbalaviele

Open Access Publications

Amino-terminal fragments from proteolytically cleaved gasdermins (GSDMs) form plasma membrane pores that enable the secretion of interleukin-1β (IL-1β) and IL-18. Excessive GSDM-mediated pore formation can compromise the integrity of the plasma membrane thereby causing the lytic inflammatory cell death, pyroptosis. We found that GSDMD and GSDME were the only GSDMs that were readily expressed in bone microenvironment. Therefore, we tested the hypothesis that GSDMD and GSDME are implicated in fracture healing owing to their role in the obligatory inflammatory response following injury. We found that bone callus volume and biomechanical properties of injured bones were significantly reduced in mice lacking …

Tourette Syndrome Research Highlights From 2020, Andreas Hartmann, Cyril Atkinson-Clement, Christel Depienne, Kevin Black

Open Access Publications

We present here research from 2020 relevant to Tourette syndrome (TS). The authors briefly summarize a few reports they consider most important or interesting.

Creation Of Philadelphia Chromosome By Crispr/Cas9-Mediated Double Cleavages On Bcr And Abl1 Genes As A Model For Initial Event In Leukemogenesis, Minori Tamai, Kenji Kamimoto, Kohei Omachi, Et Al.

2020-Current year OA Pubs

The Philadelphia (Ph) chromosome was the first translocation identified in leukemia. It is supposed to be generated by aberrant ligation between two DNA double-strand breaks (DSBs) at the BCR gene located on chromosome 9q34 and the ABL1 gene located on chromosome 22q11. Thus, mimicking the initiation process of translocation, we induced CRISPR/Cas9-mediated DSBs simultaneously at the breakpoints of the BCR and ABL1 genes in a granulocyte-macrophage colony-stimulating factor (GM-CSF) dependent human leukemia cell line. After transfection of two single guide RNAs (sgRNAs) targeting intron 13 of the BCR gene and intron 1 of the ABL1 gene, a factor-independent subline was …

All-Cause And In-Hospital Mortality After Aspirin Use In Patients Hospitalized With Covid-19: A Systematic Review And Meta-Analysis, Nischit Baral, Joshua D Mitchell, Pramod K Savarapu, Maxwell Akanbi, Bandana Acharya, Soumya Kambalapalli, Amith Seri, Krishna P Bashyal, Arvind Kunadi, Niranjan Ojha, Annabelle Santos Volgman, Tripti Gupta, Timir K Paul

2020-Current year OA Pubs

BACKGROUND: With the results of the largest randomized controlled trial (RECOVERY) and the most extensive retrospective cohort study on coronavirus disease 2019 (COVID-19) recently published, we performed a meta-analysis on the association of aspirin with mortality of COVID-19. We aimed to investigate the role of aspirin in COVID-19 hospitalizations.

MATERIALS AND METHODS: We searched PubMed, EMBASE and Cochrane databases for studies from 1 January 2020 until 20 July 2022, that compared aspirin versus non-aspirin use in hospitalized COVID-19 patients. We excluded case reports, review articles and studies on non-hospitalized COVID-19 infections. We used the inverse variance method and random effects …

Characteristics Of Antifungal Utilization For Hospitalized Children In The United States, Lourdes Eguiguren, Brian R Lee, Jason G Newland, Matthew P Kronman, Adam L Hersh, Jeffrey S Gerber, Grace M Lee, Hayden T Schwenk

2020-Current year OA Pubs

OBJECTIVE: To characterize antifungal prescribing patterns, including the indication for antifungal use, in hospitalized children across the United States.

DESIGN: We analyzed antifungal prescribing data from 32 hospitals that participated in the SHARPS Antibiotic Resistance, Prescribing, and Efficacy among Children (SHARPEC) study, a cross-sectional point-prevalence survey conducted between June 2016 and December 2017.

METHODS: Inpatients aged <18 years with an active systemic antifungal order were included in the analysis. We classified antifungal prescribing by indication (ie, prophylaxis, empiric, targeted), and we compared the proportion of patients in each category based on patient and antifungal characteristics.

RESULTS: Among 34,927 surveyed patients, 2,095 (6%) received at least 1 systemic antifungal and there were 2,207 antifungal prescriptions. Most patients had an underlying oncology or bone marrow transplant diagnosis (57%) or were premature (13%). The most prescribed antifungal was fluconazole (48%) and the …

Antibodies In Healthcare Personnel Following Severe Acute Respiratory Syndrome Coronavirus Virus 2 (Sars-Cov-2) Infection, Rachel E Bosserman, Christopher W Farnsworth, Caroline A O'Neil, Candice Cass, Daniel Park, Claire Ballman, Meghan A Wallace, Emily Struttmann, Henry Stewart, Olivia Arter, Kate Peacock, Victoria J Fraser, Philip J Budge, Margaret A Olsen, Carey-Ann D Burnham, Hilary M Babcock, Jennie H Kwon, Cdc Prevention Epicenters

2020-Current year OA Pubs

In a prospective cohort of healthcare personnel (HCP), we measured severe acute respiratory syndrome coronavirus virus 2 (SARS-CoV-2) nucleocapsid IgG antibodies after SARS-CoV-2 infection. Among 79 HCP, 68 (86%) were seropositive 14-28 days after their positive PCR test, and 54 (77%) of 70 were seropositive at the 70-180-day follow-up. Many seropositive HCP (95%) experienced an antibody decline by the second visit.

Totally Percutaneous Endovascular Repair For Ruptured Abdominal Aortic Aneurysms, Shirli Tay, Mohamed S Zaghloul, Mehreen Shafqat, Chao Yang, Kshitij A Desai, Gayan De Silva, Luis A Sanchez, Mohamed A Zayed

2020-Current year OA Pubs

PURPOSE: The PEVAR Trial demonstrated that compared to open femoral exposure, elective percutaneous endovascular AAA repair (ePEVAR) is associated with decreased perioperative morbidity and access site complications. We hypothesized that PEVAR for ruptured AAA (rPEVAR) may also improve perioperative morbidity compared to open femoral exposure (rEVAR). There are currently no reports that evaluate the utility and outcomes of rPEVAR.

MATERIALS AND METHODS: From 2015 to 2021, all patients who underwent an endovascular repair of a ruptured AAA at a single institution were included in the study and grouped into rPEVAR and rEVAR. Demographics, procedural details (successful preclose technique, conversion to …

Control Of Aging By The Renin-Angiotensin System: A Review Of C. Elegans, Drosophila, And Mammals, Brian M Egan, Andrea Scharf, Franziska Pohl, Kerry Kornfeld

2020-Current year OA Pubs

The free-living, non-parasitic nematode

Expansion Of A Novel Population Of Nk Cells With Low Ribosome Expression In Juvenile Dermatomyositis, Kinsey A Hilliard, Allison A Throm, Jeanette T Pingel, Nermina Saucier, Hani S Zaher, Anthony R French

2020-Current year OA Pubs

Juvenile dermatomyositis (JDM) is a pediatric autoimmune disease associated with characteristic rash and proximal muscle weakness. To gain insight into differential lymphocyte gene expression in JDM, peripheral blood mononuclear cells from 4 new-onset JDM patients and 4 healthy controls were sorted into highly enriched lymphocyte populations for RNAseq analysis. NK cells from JDM patients had substantially greater differentially expressed genes (273) than T (57) and B (33) cells. Upregulated genes were associated with the innate immune response and cell cycle, while downregulated genes were associated with decreased ribosomal RNA. Suppressed ribosomal RNA in JDM NK cells was validated by measuring …

Correlating Electroconvulsive Therapy Response To Electroencephalographic Markers: Study Protocol, Subha Subramanian, Alyssa K Labonte, Thomas Nguyen, Anhthi H Luong, Orlandrea Hyche, S Kendall Smith, R Edward Hogan, Nuri B Farber, Ben Julian A Palanca, Mohammadmehdi Kafashan, Cet-Rem Study Group

2020-Current year OA Pubs

INTRODUCTION: Electroconvulsive therapy (ECT) is an effective intervention for patients with major depressive disorder (MDD). Despite longstanding use, the underlying mechanisms of ECT are unknown, and there are no objective prognostic biomarkers that are routinely used for ECT response. Two electroencephalographic (EEG) markers, sleep slow waves and sleep spindles, could address these needs. Both sleep microstructure EEG markers are associated with synaptic plasticity, implicated in memory consolidation, and have reduced expression in depressed individuals. We hypothesize that ECT alleviates depression through enhanced expression of sleep slow waves and sleep spindles, thereby facilitating synaptic reconfiguration in pathologic neural circuits.

METHODS: Correlating …